The mounting prevalence of risk factors such as aging, diabetes, and hypertension, coupled with genetic factors can perturb the cellular and molecular mechanism of the aortic valves leading to calcific aortic valve disease (CAVD) and ultimately aortic stenosis. Surgical replacement of the aortic valve remains the only and the last choice for the disease. Over 30,000 aortic valves were replaced in 2009. Patients with severe aortic stenosis who do not receive surgical valve replacement have a mortality rate of 37% at one year after symptom onset. However, replacement valves are susceptible to failure, necessitating additional surgeries. There currently is no effective medical therapy for CAVD due to the unknown etiology of the disease. Therefore, a conceptual breakthrough to develop novel targets and strategies to develop a cure for CAVD is paramount. Klotho is a recently-discovered anti- aging gene and is predominately expressed in kidneys. Klotho is a secreted protein. The level of circulating klotho declines in the aged population while the prevalence of CAVD increases in the aged population. The objective of this application is to determine, in animal models, if klotho deficiency is a causal factor of CAVD and if klotho gene delivery or klotho protein supplement could serve as an effective therapeutic strategy for CAVD. We will accomplish this objective by pursuing the following two complement specific aims. (1) Determine if klotho deficiency causes CAVD and investigate its molecular mechanism. (2) Investigate the hypothesis that in vivo klotho gene or protein delivery will attenuate or reverse CAVD in senescence-accelerated mice. The proposed work is innovative and significant because it utilizes state-of-the-art approaches to address CAVD which affects a large aged population but remains poorly explored. The results will reveal a novel etiological factor for senescence-related CAVD. The proposed research will provide important insights into therapeutic strategies for CAVD.